Fabian Yap

Dynamics of Infant Gut Microbiota Are Influenced by Delivery Mode and Gestational Duration and Are Associated with Subsequent Adiposity

ABSTRACT  We found that the relatively simple microbiota of young infants shifts predictably to a more mature anaerobic microbiota during infancy and the dynamics of this shift are influenced by environmental factors. In this longitudinal study of 75 infants, we demonstrate high interindividual variability within the normal range of birth outcomes, especially in the rate of microbiota progression. Most had acquired a microbiota profile high in Bifidobacterium and Collinsella by 6 months of age, but the time point of this acquisition was later in infants delivered by caesarean section and those born after a shorter duration of gestation. Independently of the delivery mode and gestation duration, infants who acquired a profile high in Bifidobacterium and Collinsella at a later age had lower adiposity at 18 months of age. IMPORTANCE  This study shows that the acquisition of the early microbiota is strongly influenced by environmental factors such as the delivery mode and duration of gestation, even in healthy neonates. The composition of the early microbiota has been linked with long-lasting effects on health and disease. Here we show that the rate of acquisition of certain microbiota predicts adiposity at 18 months of age and so potentially the risk of later obesity. This study shows that the acquisition of the early microbiota is strongly influenced by environmental factors such as the delivery mode and duration of gestation, even in healthy neonates. The composition of the early microbiota has been linked with long-lasting effects on health and disease. Here we show that the rate of acquisition of certain microbiota predicts adiposity at 18 months of age and so potentially the risk of later obesity.

Maternal Protein Intake during Pregnancy Is Not Associated with Offspring Birth Weight in a Multiethnic Asian Population

BACKGROUND Maternal diet during pregnancy can influence fetal growth. However, the relation between maternal macronutrient intake and birth size outcomes is less clear. OBJECTIVE We examined the associations between maternal macronutrient intake during pregnancy and infant birth size. METHODS Pregnant women (n = 835) from the Singapore GUSTO (Growing Up in Singapore Towards healthy Outcomes) mother-offspring cohort were studied. At 26-28 wk of gestation, the macronutrient intake of women was ascertained with the use of 24 h dietary recalls and 3 d food diaries. Weight, length, and ponderal index of their offspring were measured at birth. Associations were assessed by substitution models with the use of multiple linear regressions. RESULTS Mean ± SD maternal energy intake and percentage energy from protein, fat, and carbohydrates per day were 1903 ± 576 kcal, 15.6% ± 3.9%, 32.7% ± 7.5%, and 51.6% ± 8.7% respectively. With the use of adjusted models, no associations were observed for maternal macronutrient intake and birth weight. In male offspring, higher carbohydrate or fat intake with lower protein intake was associated with longer birth length (β = 0.08 cm per percentage increment in carbohydrate; 95% CI: 0.04, 0.13; β = 0.08 cm per percentage increment in fat; 95% CI: 0.02, 0.13) and lower ponderal index (β = -0.12 kg/m(3) per percentage increment in carbohydrate; 95% CI: -0.19, -0.05; β = -0.08 kg/m(3) per percentage increment in fat; 95% CI: -0.16, -0.003), but this was not observed in female offspring (P-interaction < 0.01). CONCLUSIONS Maternal macronutrient intake during pregnancy was not associated with infant birth weight. Lower maternal protein intake was significantly associated with longer birth length and lower ponderal index in male but not female offspring. However, this finding warrants further confirmation in independent studies. This trial was registered at clinicaltrials.gov as NCT01174875.

HIF3A association with adiposity: the story begins before birth

Aim: Determine if the association of HIF3A DNA methylation with weight and adiposity is detectable early in life. Material & methods: We determined HIF3A genotype and DNA methylation patterns (on hybridization arrays) in DNA extracted from umbilical cords of 991 infants. Methylation levels at three CpGs in the HIF3A first intron were related to neonatal and infant anthropometry and to genotype at nearby polymorphic sites. Results & conclusion: Higher methylation levels at three previously described HIF3A CpGs were associated with greater infant weight and adiposity. The effect sizes were slightly smaller than those reported for adult BMI. There was also an interaction within cis-genotype. The association between higher DNA methylation at HIF3A and increased adiposity is present in neonates. In this study, no particular prenatal factor strongly influenced HIF3A hypermethylation. Our data nonetheless suggest shared prenatal influences on HIF3A methylation and adiposity.

Rate of establishing the gut microbiota in infancy has consequences for future health

The gut of the human neonate is colonized rapidly after birth from an early sparse and highly distinct microbiota to a more adult-like and convergent state, within 1 to 3 years. The progression of colonizing bacterial species is non-random. During the first months of life several shifts commonly occur in the species prevalent in our guts. Although the sequential progression of these species is remarkably consistent across individuals and geographies, there is inter-individual variation in the rate of progression. Our study and others suggest that the rate is influenced by environmental factors, and influences our future health. In this article, we review our recent contribution to cataloging the developing infant gut microbiota alongside other important recent studies. We suggest testable hypotheses that arise from this synthesis.

Infant feeding effects on early neurocognitive development in Asian children

BACKGROUND Breastfeeding has been shown to enhance global measures of intelligence in children. However, few studies have examined associations between breastfeeding and specific cognitive task performance in the first 2 y of life, particularly in an Asian population. OBJECTIVE We assessed associations between early infant feeding and detailed measures of cognitive development in the first 2 y of life in healthy Asian children born at term. DESIGN In a prospective cohort study, neurocognitive testing was performed in 408 healthy children (aged 6, 18, and 24 mo) from uncomplicated pregnancies (i.e., birth weight >2500 and <4000 g, gestational age ≥37 wk, and 5-min Apgar score ≥9). Tests included memory (deferred imitation, relational binding, habituation) and attention tasks (visual expectation, auditory oddball) as well as the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). Children were stratified into 3 groups (low, intermediate, and high) on the basis of breastfeeding duration and exclusivity. RESULTS After potential confounding variables were controlled for, significant associations and dose-response relations were observed for 4 of the 15 tests. Higher breastfeeding exposure was associated with better memory at 6 mo, demonstrated by greater preferential looking toward correctly matched items during early portions of a relational memory task (i.e., relational binding task: P-trend = 0.015 and 0.050 for the first two 1000-ms time bins, respectively). No effects of breastfeeding were observed at 18 mo. At 24 mo, breastfed children were more likely to display sequential memory during a deferred imitation memory task (P-trend = 0.048), and toddlers with more exposure to breastfeeding scored higher in receptive language [+0.93 (0.23, 1.63) and +1.08 (0.10, 2.07) for intermediate- and high-breastfeeding groups, respectively, compared with the low-breastfeeding group], as well as expressive language [+0.58 (-0.06, 1.23) and +1.22 (0.32, 2.12) for intermediate- and high-breastfeeding groups, respectively] assessed via the BSID-III. CONCLUSIONS Our findings suggest small but significant benefits of breastfeeding for some aspects of memory and language development in the first 2 y of life, with significant improvements in only 4 of 15 indicators. Whether the implicated processes confer developmental advantages is unknown and represents an important area for future research. This trial was registered at www.clinicaltrials.gov as NCT01174875.

Association between perinatal methylation of the neuronal differentiation regulator HES1 and later childhood neurocognitive function and behaviour

Background Early life environments induce long-term changes in neurocognitive development and behaviour. In animal models, early environmental cues affect neuropsychological phenotypes via epigenetic processes but, as yet, there is little direct evidence for such mechanisms in humans. Method We examined the relation between DNA methylation at birth and child neuropsychological outcomes in two culturally diverse populations using a genome-wide methylation analysis and validation by pyrosequencing. Results Within the UK Southampton Women’s Survey (SWS) we first identified 41 differentially methylated regions of interest (DMROI) at birth associated with child’s full-scale IQ at age 4 years. Associations between HES1 DMROI methylation and later cognitive function were confirmed by pyrosequencing in 175 SWS children. Consistent with these findings, higher HES1 methylation was associated with higher executive memory function in a second independent group of 200 SWS 7-year-olds. Finally, we examined a pathway for this relationship within a Singaporean cohort (n = 108). Here, HES1 DMROI methylation predicted differences in early infant behaviour, known to be associated with academic success. In vitro, methylation of HES1 inhibited ETS transcription factor binding, suggesting a functional role of this site. Conclusions Thus, our findings suggest that perinatal epigenetic processes mark later neurocognitive function and behaviour, providing support for a role of epigenetic processes in mediating the long-term consequences of early life environment on cognitive development.

Maternal Folate Status, but Not That of Vitamins B-12 or B-6, Is Associated with Gestational Age and Preterm Birth Risk in a Multiethnic Asian Population

BACKGROUND Maternal folate, vitamin B-12, and vitamin B-6 concentrations during pregnancy have been shown to influence birth outcomes, but the evidence is inconclusive. OBJECTIVE We aimed to examine the associations of maternal B-vitamin status with gestational age, birth weight, and length in a birth cohort study in Singapore. METHODS Maternal blood samples (n = 999) collected during weeks 26-28 of gestation were assayed for plasma folate, vitamin B-12, and vitamin B-6 concentrations. Birth weight and gestational age data were obtained from hospital records, and other anthropometric variables were measured within 72 h after birth. Relations between B-vitamin status and birth outcomes were assessed by linear or logistic regression with adjustment for potential confounders. RESULTS Median (IQR) plasma concentrations were 34.4 (24.5-44.6) nmol/L for folate, 209 (167-258) pmol/L for vitamin B-12, and 61.8 (25.9-113) nmol/L for vitamin B-6. We found that higher plasma folate concentrations were associated with a longer gestational age (0.12 wk per SD increase in folate; 95% CI: 0.02, 0.21) and tended to be associated with lower risk of all preterm birth (delivery at <37 wk of gestation; OR: 0.79; 95% CI: 0.63, 1.00) and spontaneous preterm birth (OR: 0.76; 95% CI: 0.56, 1.04). Overall, concentrations of maternal folate, vitamin B-12, and vitamin B-6 were not independently associated with birth weight or being born small for gestational age (SGA; birth weight <10th percentile for gestational age). CONCLUSIONS Higher maternal folate concentrations during late pregnancy were associated with longer gestational age and tended to be associated with a lower risk of preterm birth in this multiethnic Asian population. In contrast, the results of our study suggested little or no benefit of higher folate concentrations for reducing the risk of SGA or of higher vitamin B-6 and vitamin B-12 concentrations for reducing the risk of preterm birth or SGA.

The association of maternal vitamin D status with infant birth outcomes, postnatal growth and adiposity in the first 2 years of life in a multi-ethnic Asian population: the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort study

Maternal vitamin D status during pregnancy has been associated with infant birth and postnatal growth outcomes, but reported findings have been inconsistent, especially in relation to postnatal growth and adiposity outcomes. In a mother-offspring cohort in Singapore, maternal plasma vitamin D was measured between 26 and 28 weeks of gestation, and anthropometric measurements were obtained from singleton offspring during the first 2 years of life with 3-month follow-up intervals to examine birth, growth and adiposity outcomes. Associations were analysed using multivariable linear regression. Of a total of 910 mothers, 13·2 % were vitamin D deficient (<50 nmol/l) and 26·5 % were insufficient (50-75 nmol/l). After adjustment for potential confounders and multiple testing, no statistically significant associations were observed between maternal vitamin D status and any of the birth outcomes - small for gestational age (OR 1·00; 95 % CI 0·56, 1·79) and pre-term birth (OR 1·16; 95 % CI 0·64, 2·11) - growth outcomes - weight-for-age z-scores, length-for-age z-scores, circumferences of the head, abdomen and mid-arm at birth or postnatally - and adiposity outcomes - BMI, and skinfold thickness (triceps, biceps and subscapular) at birth or postnatally. Maternal vitamin D status in pregnancy did not influence infant birth outcomes, postnatal growth and adiposity outcomes in this cohort, perhaps due to the low prevalence (1·6 % of the cohort) of severe maternal vitamin D deficiency (defined as of <30·0 nmol/l) in our population.

Faster eating rates are associated with higher energy intakes during an ad libitum meal, higher BMI and greater adiposity among 4-5 year-old children: results from the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) cohort

Faster eating rates are associated with increased energy intake, but little is known about the relationship between childrens eating rate, food intake and adiposity. We examined whether children who eat faster consume more energy and whether this is associated with higher weight status and adiposity. We hypothesised that eating rate mediates the relationship between child weight and ad libitum energy intake. Children (n 386) from the Growing Up in Singapore Towards Healthy Outcomes cohort participated in a video-recorded ad libitum lunch at 4·5 years to measure acute energy intake. Videos were coded for three eating-behaviours (bites, chews and swallows) to derive a measure of eating rate (g/min). BMI and anthropometric indices of adiposity were measured. A subset of children underwent MRI scanning (n 153) to measure abdominal subcutaneous and visceral adiposity. Children above/below the median eating rate were categorised as slower and faster eaters, and compared across body composition measures. There was a strong positive relationship between eating rate and energy intake (r 0·61, P<0·001) and a positive linear relationship between eating rate and childrens BMI status. Faster eaters consumed 75 % more energy content than slower eating children (Δ548 kJ (Δ131 kcal); 95 % CI 107·6, 154·4, P<0·001), and had higher whole-body (P<0·05) and subcutaneous abdominal adiposity (Δ118·3 cc; 95 % CI 24·0, 212·7, P=0·014). Mediation analysis showed that eating rate mediates the link between child weight and energy intake during a meal (b 13·59; 95 % CI 7·48, 21·83). Children who ate faster had higher energy intake, and this was associated with increased BMI z-score and adiposity.

Associations of gestational glycemia and prepregnancy adiposity with offspring growth and adiposity in an Asian population

BACKGROUND Maternal obesity and hyperglycemia increase risk of obesity and diabetes in offspring later in life. OBJECTIVE We examined the relation between gestational glycemia and prepregnancy body mass index (ppBMI) with offspring growth in an Asian mother-offspring cohort. DESIGN Pregnant mothers undertook a 75-g 2-h oral-glucose-tolerance test at 26-28 wk of gestation. In 937 singleton offspring, ≤9 serial measurements of weight and length were obtained from birth until 36 mo of age. RESULTS Gestational fasting plasma glucose (FPG) was positively associated with birth weight (B: 0.17; 95% CI: 0.10, 0.24; P < 0.001) and birth BMI (B: 0.15; 95% CI: 0.06, 0.40; P = 0.001) but not at ≥3 mo of age. In contrast, maternal ppBMI was positively associated with birth variables and conditional growth in weight and BMI in the first 36 mo of life. However, gestational FPG and prepregnancy obesity status interacted significantly for the association with offspring growth and overweight status in the first 36 mo of life (P-interaction < 0.01). In nonobese mothers, each unit increase in gestational FPG was associated with increased offspring weight (B: 0.08; 95% CI: 0.008, 0.16; P = 0.03) and BMI (B: 0.08; 95% CI: 0.003, 0.15; P = 0.04) as well as increased risk of overweight in the first 36 mo of life (OR: 1.36; 95% CI: 1.10, 1.68). However, in obese mothers, each unit increase in gestational FPG was associated with decreased offspring weight (B: -0.01; 95% CI: -0.02, -0.003) and BMI (B: -0.008; 95% CI: -0.01, -0.002) velocity (P < 0.01 for both) and decreased risk of overweight (OR: 0.59; 95% CI: 0.41, 0.86) in the first 36 mo of life. CONCLUSIONS Prepregnancy adiposity was associated with offspring growth in early childhood. Although pooled analyses showed no demonstrable difference by 3 mo of age, there were contrasting and opposite associations of gestational glycemia with weight and BMI in the first 36 mo of life in offspring of nonobese and obese mothers separately. This study was registered at clinicaltrials.gov as NCT01174875.